Research design and methods will be pursued to accomplish three specific aims, which are centered on peptides, proteins, lipids, and nucleic acids. Mass spectrometric instrumentation, method, and computer software will be developed to facilitate proteomics and to expedite the determination of the structure and properties of peptides and proteins. An important goal is the muscle proteome. Resident at Washington University is the necessary personnel and equipment infrastructure to determine this proteome and make unique contributions to understanding metabolic and neuromuscular diseases. The means to achieving this specific aim are to implement computer and chemical means to enhance information content of mass spectrometric methods in proteomics, to develop hydrogen/deuterium amide exchange to probe protein structure and interactions, and to develop Fourier transform mass spectrometric instrumentation for improving mass resolving power and mass-measurement accuracy for peptides and proteins. The second analyte focus is complex lipids, an area of long-standing and productive interest at Washington University. Structure determination of this class of analytes will be pursued by developing new methods and comparing cutting-edge instruments for analysis of lipids in complex mixtures. To facilitate interpretation of structural information, a major experimental and theoretical effort will be continued to understand the mechanisms of lipid fragmentation in mass spectrometry. Better means of determining lipid structure will have major impact in understanding diabetes mellitus, atherosclerotic cardiovascular disease, and lipotoxicity. The third analyte is nucleic acids, and the goal is to use mass spectrometry to determine the structures of normal and damaged oligonucleotides and the mechanisms of the fragmentations that underpin structure determination. The research has important implications in understanding the origins of a wide variety of cancers. Building on the foundation of the efforts in research and methods will be a large number of collaborations in biophysics and in various human diseases. The core and collaborative research will also be complemented by active programs in service, training, and dissemination.